CUL4B, which acts as a scaffold protein in CUL4B-RING ubiquitin ligase (CRL4B) complexes, participates in a variety of biological processes. Previous studies have shown that CUL4B is often overexpressed and exhibits oncogenic activities in a variety of solid tumors. However, the roles and the underlying mechanisms of CUL4B in bladder cancer (BC) were poorly understood. Here, we showed that CUL4B levels were overexpressed and positively correlated with the malignancy of BC, and CUL4B could confer BC cells increased motility, invasiveness, stemness, and chemoresistance. The PIK3CA/AKT pathway was identified as a critical downstream mediator of CUL4B-driven oncogenicity in BC cells. Furthermore, we demonstrated that CRL4B epigenetically repressed the transcription of miR-372/373, via catalyzing monoubiquitination of H2AK119 at the gene cluster encoding miR-372/373, leading to upregulation of PIK3CA and activation of AKT. Our findings thus establish a critical role for the CUL4B-miR-372/373-PIK3CA/AKT axis in the pathogenesis of BC and have important prognostic and therapeutic implications in BC.

CUL4B 作为 CUL4B-RING 泛素连接酶 (CRL4B) 复合物中的支架蛋白，参与多种生物过程。先前的研究表明，CUL4B 在各种实体瘤中经常过表达并表现出致癌活性。然而，人们对 CUL4B 在膀胱癌 (BC) 中的作用和潜在机制知之甚少。在这里，我们发现 CUL4B 水平过表达并且与 BC 的恶性程度呈正相关，并且 CUL4B 可以赋予 BC 细胞增加的运动性、侵袭性、干性和化学抗性。PIK3CA/AKT 通路被确定为 BC 细胞中 CUL4B 驱动的致癌性的关键下游介质。此外，我们证明了 CRL4B 表观遗传抑制了 miR-372/373 的转录，通过在编码 miR-372/373 的基因簇上催化 H2AK119 的单泛素化，导致 PIK3CA 的上调和 AKT 的激活。因此，我们的研究结果确定了 CUL4B-miR-372/373-PIK3CA/AKT 轴在 BC 发病机制中的关键作用，并且在 BC 中具有重要的预后和治疗意义。